Modulation of sensory processing by corticofugal (CRTF) projections has been suggested to play a vital role during active sensing. Indeed retrograde CRTF projections from upstream cortical areas (such as auditory, visual and anterior piriform cortex - aPC) to early structures (the thalamus and the olfactory bulb - OB) often outnumber axons carrying information in the anterograde, upstream direction and a variety of studies reveal effects of cortical feedback on upstream transmission of information from olfactory bulb/thalamus to cortex. However, the specific role of CRTF projections has remained largely undefined and is a major open question in sensory neurobiology. In this proposal we test the hypothesis that mitral cell odor responses in the olfactory bulb are modulated by behavioral context, mediated by CRTF projections from piriform cortex. We will work at two complementary levels: neural recording in the awake-behaving animal (Aim 1) and patch clamp recording in corticofugally-modulated brain slices (Aim 2). The proposal utilizes optogenetic techniques in recordings from awake, behaving animals and brain slices to examine olfactory CRTF modulation. This will be accomplished in two specific aims: 1. Test the hypothesis that mitral cell firing in response to odorants is modulated by corticofugal input from piriform cortex controlled by behavioral context. 2. Test the hypothesis that corticofugal inputs from piriform cortex modulate mitral cell firing through specific alterations in the mitral cell/granule cell network. Taken together, we expect that these studies will reveal novel functions for CRTF projections to the bulb that could be involved in modulating the signal-to-noise of the MC output in a behavioral context-dependent fashion. PUBLIC HEALTH RELEVANCE: In humans, disorders of the sense of smell are encountered in diseases such as Alzheimer's, bipolar depression and schizophrenia. This grant will study corticofugal feedback modulation of signal processing in the olfactory bulb, a fundamental process that plays an important role in olfaction.